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Yale researchers uncover key regulator of weight-gain suggesting a treatment target for metabolic disorders

A Yale research team found that a protein called, augmentor-alpha, is a key regulator of body weight in mice. (Picture: Obese mice (right) and normal-sized mice (left) in a study on induced-feeding behaviors. Credit: Georgejason/iStock/Getty Images Plus).

According to Yale researchers, protein known as augmentor-alpha regulates body weight in mice, an understanding that might lead to novel therapies for metabolic illnesses.

Because of its link to cancer, the group of researchers chose to dig more into augmentor-alpha as a possible mechanism for metabolic disorders. The protein binds to and activates the anaplastic lymphoma kinase receptor (ALK), a molecule that, when mutated, causes a number of human malignancies, including pediatric neuroblastoma, B-cell lymphomas, and some lung cancers.

To learn more about this protein and its physiological function, the Yale researchers decided to first figure out where it was most often found. They discovered that augmentor-alpha was most highly expressed in the hypothalamus area of the brain in mice, which is the area associated with appetite and feeding control.

More specifically, the team discovered that augmentor-alpha was expressed in cells known as agouti-related peptide (AgRP) neurons, which induce appetite.

Co-author of the study, Tamas Horvath, told Yale News, “”AgRP neurons are so important for feeling hunger that without them, you wouldn’t eat. You’d die. So when it became clear that augmentor-alpha was dominantly expressed in these neurons, it immediately suggested that augmentor-alpha was involved in metabolism.”

The researchers uncovered more evidence of a relationship between augmentor-alpha and metabolic activity when they discovered that fasting enhanced augmentor-alpha expression in these neurons.

The researchers subsequently looked at mice that were completely devoid of the protein. Whether they ate a regular or high-fat diet, mice lacking augmentor-alpha weighed less than normal mice. They were also more physically active than normal mice, but they didn’t eat considerably more food.

When mice were deprived of food, they conserved energy and minimized their physical activity. However, the animals that lacked augmentor-alpha remained quite active while fasting, suggesting that the protein is a critical signal for energy conservation.

“Fasting appeared to be a signal to make more of this protein,” added Joseph Schlessinger, founding director of Yale’s Cancer Biology Institute. “From what we observed in this study, we think one of augmentor-alpha’s roles in the body is to slow down metabolism when there’s a lack of food.” It’s like it is saying, ‘You don’t have food, don’t expend so much energy.'”

The study was published in PNAS on April 11th, 2022.

Abstract. Augmentor α and β (Augα and Augβ) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augα functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augα fragment and monomeric Augβ also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Augα and Augβ are poorly understood. Here, we investigate the physiological roles of Augα and Augβ by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augα single knockout and double knockout of Augα and Augβ exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augα-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augβ-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Augα is robustly expressed and metabolically regulated in agouti-related peptide (AgRP) neurons, cells that control whole-body energy homeostasis in part via their projections to the paraventricular nucleus (PVN). Moreover, both Alk and melanocortin receptor-4 are expressed in discrete neuronal populations in the PVN and are regulated by projections containing Augα and AgRP, respectively, demonstrating that two distinct mechanisms that regulate pigmentation operate in the hypothalamus to control body weight. These experiments show that Alk-driven cancers were co-opted from a neuronal pathway in control of body weight, offering therapeutic opportunities for metabolic diseases and cancer.

Ahmed M, Kaur N, Cheng Q, Shanabrough M, Tretiakov EO, Harkany T, Horvath TL, Schlessinger J. A hypothalamic pathway for Augmentor α-controlled body weight regulation. Proc Natl Acad Sci U S A. 2022 Apr 19;119(16):e2200476119. doi: 10.1073/pnas.2200476119. Epub 2022 Apr 11. PMID: 35412887.

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